Opioid analgesics have been used for centuries and remain to this day the most potent and reliable analgesic agents. They are used routinely and effectively for the treatment of acute and chronic pain. Currently, approximately 90% of patients with chronic pain receive opioids. Opioids not only provide potent analgesia but also reduce anxiety and produce mild sedation and a palpable sense of well-being, often to the point of euphoria.
Unfortunately, prolonged administration of opioid analgesics causes physical dependence and addiction. Physical dependence is a state of physiological adaption manifested by a withdrawal syndrome produced by abrupt discontinuation of a medication. Addiction is a chronic neurobiological disease resulting in the use of a drug for non-therapeutic purposes. Addiction is progressive and can result in disability or premature death.
There are other problems associated with the chronic use of opioid analgesics including, but not limited to, the development of antinociceptive tolerance. Tolerance is a state of adaptation in which exposure to a drug induces changes that result in diminution of its effects over time. Tolerance of the drug require use of higher doses over time to elicit the same level of analgesia.
High doses of opioids result in serious side effects such as impairment of mental alertness, sedation, somnolence, dizziness, nausea, vomiting, urinary retention, constipation, pruritus and others. Unfortunately, use of opioids for pain treatment has now been transformed to a social problem similar to problems associated with methamphetamine, cocaine or other illegal drugs.
Opioid abuse is an epidemic all over the world. It is believed that the number of new opioid abusers had increased by 225% between 1992 and 2000. In fact, in 2010 there were as many as 2.4 million opioid abusers in the United States alone. The U.S. Centers for Disease Control and Prevention (CDC) reported that drug-overdose deaths reached a new high in 2014, totaling 47,055 people in which 60% was due to opioids.
Opioid receptor antagonists (i.e., “opioid antagonists”) are drugs that bind to the opioid receptors, typically with higher affinity than agonists. Unlike agonists, antagonists do not activate the receptors to which they bind. Thus, opioid antagonists are often used to block the receptor from the action of agonists to counteract life-threatening depression of the central nervous and respiratory systems. Accordingly, opioid antagonists are often used to treat opioid overdose and opioid dependency.
Opioid receptor antagonists modulate or attenuate numerous central and peripheral effects including opioid abuse, the development of tolerance and dependence, and opioid-induced constipation, alcohol and cocaine abuse, depression, and immune responses. The diverse therapeutic applications of μ-opioid receptor antagonists include opioid-overdose-induced respiratory depression, opioid and cocaine abuse, alcohol dependence, smoking cessation, obesity, psychosis and for therapies for dyskinesia associated with Parkinson's disease.
Commonly known opioid antagonists include naltrexone, naloxone and nalmefene which have therapeutic utility in a variety of conditions. Opioid antagonists effectively block the receptor from the action of both naturally occurring agonists (e.g., morphine, codeine, thebaine) and synthetic agonists (e.g., fentanyl, pethidine, levorphanol, methadone, tramadol, dextropropoxyphene) and uses include counteracting life-threatening depression of the central nervous and respiratory systems.
During the last two decades only Alvimopan, a peripherally acting μ-opioid receptor antagonist for the treatment of postoperative ileus has been approved as new drug, and some azabicyclohexane derivatives and series of bi(hetero)aryl ethers as biological tools have been proposed as new chemical entities in this class of compounds.
In a commonly assigned PCT Patent Application No. PCT/US15/46585 and the corresponding U.S. patent application Ser. No. 14/834,185, both of which were filed on Aug. 24, 2015, and are incorporated herein by reference in their entirety, treatment of various clinical conditions using substituted 1-arylalkyl-4-acylaminopiperidine compounds are discussed, such as those associated with opioid abuse, the development of opioid tolerance and dependence, opioid-induced constipation, cocaine abuse, depression, and immune responses, opioid-overdose-induced respiratory depression, alcohol dependence, smoking cessation, obesity, psychosis, dyskinesia associated with Parkinson's disease, Raynaud's disease, hypertension, scleroderma, anxiety and panic disorders.
Despite the various opioid antagonists that are currently available, there is a continuing need for other opioid antagonists. In addition, there is a need for a compound that provides potent analgesia without causing undesired side-effects including addiction and dependency.